Generally, a fluid bed reactor, may comprise a vertical reactor with an inlet, an outlet, a fluid bed of particles (a solid phase), and a liquid. The liquid is introduced at the inlet and dispersed, optionally through a gas head in case of down-flow reactors, on the bed of solid phase particles, which are suspended and fluidised by the liquid. The liquid is conducted through the bed and a pool of reacted and/or unreacted fluid is let out at the outlet.
Up-flow fluid reactors have liquid inlet at or near the bottom of the reactor and solid phase particles of specific gravity larger than that of the liquid.
Down-flow fluid bed reactors have liquid inlet at or near the top of the reactor and solid phase particles of specific gravity less than that of the liquid.
The suspended and fluidised solid phase particles may be impermeable to the fluid or completely permeable to the fluid and substances present in the fluid. The suspended and fluidised solid phase particles may further be reactive or may carry immobilised reactive components selected for solid phase chemical or physical processes with one or more components of the fluid in procedures such as enzymatic reactions; fermentation; ion-exchange and affinity chromatography; filtration; adsorption; chemical catalysis; immunosorption; solid-phase peptide and protein synthesis; and microbiological growth of micro-organisms.
In fluid bed reactors partially solving the problems of packed bed columns, i.e. the problems of suspended matter clogging up the solid-phase bed which increases the back pressures and compresses the bed, disturbing the flow through the bed, the solid phase particles are kept in a free, fluid phase by applying a flow having an opposite direction to the direction of the relative movement of the solid phase particles. Thus, solid phase particles having a density larger than the liquid and moving downwards due to gravity may be kept in a free, fluid phase by an upwards flow of liquid. Also, solid phase particles having a density less than the liquid and thus moving upwards may due to buoyancy be kept in a free, fluid phase by a downwards flow of liquid.
In order to carry out solid phase chemical or physical processes in a fluid bed reactor, an even and smooth distribution of fluid in the fluid bed without back-mixing is often desired. However, fluid bed reactors known in the art do not have efficient means known per se to avoid formation of channels as well as unwanted turbulence and back-mixing in the solid phase particle bed. Especially when the task is to distribute the liquid in large industrial scale reactors (e.g. reactors with cross-sectional areas of more than 0.5-1 m2) it becomes increasingly difficult to obtain a satisfactory distribution of the fluid.
An interesting field of application of fluid bed reactors is EBA.
EBA is an abbreviation for Expanded Bed Adsorption. This is a technology used widely within the biotechnology industries, for example for the production of pharmaceuticals and diagnostic products and in particular for the separation and purification of a broad range of bio-molecules, for example enzymes, proteins, peptides, DNA and plasmids from a vast range of extracts and raw materials, many of which are crude and unclarified. The present invention particularly relates to a new way of introducing the fluid to be processed into an expanded bed adsorption contactor.
The term expanded bed is used to describe a special case of a fluid bed (or fluidised bed) where turbulence or back-mixing of the fluid in the suspended bed of solid phase particles is at a minimum. Another term for this situation is that the fluid passes the expanded bed With “plug flow” and thus resembles the flow pattern in a packed bed wherein turbulence and back-mixing are practically absent.
A traditional purification process for a mixture comprising one or several target molecules could be purification on a packed column (i.e. not EBA), however this requires multiple operational steps such as filtration and centrifugation in order to ensure that impurities in suspension and particulates (for example colloids, whole cells, cell walls, protein aggregates) are removed before the mixture is applied to a suitable packed column. These steps are necessary in order to avoid clogging of the packed column. In the packed column, a given chromatographic medium is present for binding of molecule(s) which are generally the target of the purification, but alternatively can also be used for binding impurities. This chromatographic medium can be adapted to various purification purposes.
The main principle in EBA is to keep the chromatographic medium fluidised and thereby allow particulate impurities, suspended solids and colloidal materials to pass through the column. By using the EBA technology, it is in many instances possible to avoid the above-mentioned operational steps (i.e. those used before packed bed chromatography) before application of the raw material to the column. In this manner, time and expenses for these processes are reduced making EBA a valuable technology, which is economically recommendable for the purification of a large number of different bio-molecules. In addition, productivity and overall yield can be expected to be improved when compared to traditional processing using packed beds.
In order to utilise the EBA technology, an EBA column used to contain a suitable chromatographic medium is required in conjunction with a suitable fluid distribution mechanism.
A brief presentation of the steps generally used in the EBA technology will be given in the following (assuming it is an up-flow process with solid phase particles more dense than the fluid).                1. An adequate quantity of solid phase adsorbent is placed in an EBA column (i.e. the fluid bed rector).        2. Fluid flow through the adsorbent from below is initiated by pumping the liquid to be processed through a fluid distributor. The adsorbent is thereby fluidised (expanded).        3. The adsorbent is rinsed in the column and the conductivity (i.e. salt concentration) and pH are adjusted to what is required to allow binding of the target to the adsorbent.        4. Raw material (i.e. the feedstock) is applied to the expanded bed of adsorbents and the target molecule(s) are bound.        5. The remaining raw material is rinsed out from the column using a wash fluid.        6. The target molecule is eluted off the adsorbent medium by applying a fluid that weakens the interaction with the adsorbent. The elution of the target molecule may be performed after packing the chromatographic adsorbent and reversing the flow direction in the column or the elution may be performed in the expanded bed state.        7. The chromatographic adsorbent is finally (optionally) rinsed and regenerated.        
Before the raw material is applied to the column, it should be ensured that expansion of the bed of adsorbent media is stable (i.e. that plug flow like fluid rise is obtained in the column without unwanted turbulence or back mixing of the fluid). The most reliable way of checking seems to be determining the number of theoretical plates by examining the residence time distribution following addition of a tracer. Such methods are well known to those familiar with examining the performance of reactors and particularly to those versed in the art of expanded bed adsorption (for example see the hand book “Expanded Bed Adsorption” by Pharmacia Biotech, Edition AA, page 14; or Levenspiel, O. 1999. Chemical reaction engineering, 3rd ed. John Wiley and Sons, Inc. N.Y.). A satisfying total number of theoretical plates in a column indicating a low degree of back-mixing and fluid flow characteristics suitable for an EBA process is generally in the range of 25 to 30 plates or more (see for example “Expanded Bed Adsorption” by Pharmacia Biotech, Edition AA, page 16). In addition, it is generally considered that 50-100 theoretical plates per meter sedimented bed height is satisfactory. Furthermore, visual inspection of the bed particularly using dyes or colored tracers can provide valuable qualitative information about the presence of channels or jet streams in the column. If the solid phase media move only in small circles, channels are not observed and local jet streams of fluid largely devoid of media cannot be seen, this is a good indication that the adsorbent media is expanded in a stable manner.
If an EBA column is not expanded in a stable way and has a plug flow fluid rise, the adsorption efficiency may be low and the whole process economy may be impaired. In analogy, the same will be true for a broad range of other fluid bed and expanded bed reactions not related to adsorption e.g. (continuous) enzymatic reactions and chemical catalysis, chemical synthesis of e.g. peptides and polynucleotides. In these cases, an unstable expansion with turbulence and back-mixing may result in a high loss of unreacted chemical building blocks at the outlet of the column and potentially a slower reaction rate. Also, chemical reaction equilibrium may not be reached or may shifted in an unfavourable direction.
Further information about EBA technology can be found in the book “Expanded Bed Adsorption” by Pharmacia Biotech, Edition AA.